Vitamin B12 Catalyzed Atom Transfer Radical Addition

Article abstract of DOI:10.1021/acs.orglett.7b03699

Vitamin B₁₂, a natural Co-complex, catalyzes atom transfer radical addition (ATRA) of organic halides to olefins. The established conditions were found to be very selective, with atom transfer radical polymerization (ATRP) occurring only in the case of acrylates.

Full text of DOI:10.1021/acs.orglett.7b03699

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Vitamin B12 Catalyzed Atom Transfer Radical Addition
́
Keith o Proinsias,* Agnieszka Jackowska, Katarzyna Radzewicz, Maciej Giedyk, and Dorota Gryko*
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: Vitamin B12, a natural Co-complex, catalyzes
atom transfer radical addition (ATRA) of organic halides to
olefins. The established conditions were found to be very
selective, with atom transfer radical polymerization (ATRP)
occurring only in the case of acrylates.
itamin B12 (cobalamin, B12, 1, Figure 1) is a highly
functionalized, benign molecule with a very unique and
bonds in a single reaction system.5 Unfortunately, the majority
of these approaches require high metal-catalyst loading (10−
30 mol % in relation to the alkene) to achieve high selectivity
and the need for reagents such as peroxides, organotin
reagents, and triethyl boron, as well as harsh reaction
conditions, e.g. high temperature.6 Other commonly used
reagents include TiCl3, copper, iron bimetallic Rh−Ru
complexes, and chromium(II) acetate, to name a few.7 On
the other hand, Melchiorre et al. demonstrated that by using
only p-anisaldehyde (20 mol %) in the presence of 2,6-lutidine
and light, it is possible to perform selective intermolecular
ATRA reactions of primarily bromo-malonate and -propanate
type haloalkanes with aliphatic olefins.8
V
To date, cobalt complexes are often applied as catalysts in
atom transfer radical polymerization (ATRP) reactions. In
contrast, selective Co-catalyzed ATRA reactions, to the best of
our knowledge, are unexplored.9 We envisaged that vitamin
B12, a benign cobalt complex, might be a suitable catalyst for
this process. This concept holds a multitude of challenges, with
the obvious concern being that the preferred route for B12-
catalyzed reactions involving organic halides is dehalogenation.
Figure 1. Vitamin B12 1 and heptamethyl cobyrinate (CN)(H2O)-
Cby(OMe)7 2.
stable cobalt center.1 Upon reduction of cobalamin or its
derivatives, either radical Co(II) or supernucleophilic Co(I)
species is formed, which upon reacting with radicals or
electrophiles ultimately leads to alkyl cobalamins.2 Typically,
B12-catalyzed reactions adhere to a radical mechanism and
numerous chemical transformations have been developed in
this area, evolving B12-catalysis beyond its natural coenzyme
functions (homocoupling, methylation, isomerization, etc.).1−3
But intermolecular reactions involving organic halides have
been rather limited due to undesirable side reactions, i.e.
dehalogenation and homocoupling, taking precedence.2,4
Since its discovery in 1937 by Kharasch, atom transfer
radical addition (ATRA, Scheme 1) has made considerable
advances developing into a unique and highly desirable
method of generating carbon−carbon and carbon−halogen
Scheme 2. Model Reaction of Benzyl Bromide (3a) with
Phenyl Vinyl Sulfone (4)
The initial exploratory experiments showed that ATRA only
occurs if the reaction is conducted in a microwave reactor10
using either THF or toluene as a solvent, and NaBH4 as a
reducing agent preferably over the more commonly used zinc
for the efficient reduction of the catalyst.2 Heptamethyl
cobyrinate11 (2, Figure 1) was the catalyst of choice for this
Scheme 1. Atom Transfer Radical Addition (ATRA)
Received: November 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03699
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope and Limitation Studies
a
Conditions: organic halide (0.84 mmol), olefin (0.28 mmol), (CN)(H2O)Cby(OMe)7 (2, 27 mg, 0.025 mmol, 8 mol %), NaBH4 (20 mg, 0.5
mmol), Cs2CO3 (85 mg, 0.26 mmol), toluene (0.5 mL), 90 °C MW 300 W, 40 min. Conditions for acrylates 11a−c: m-methoxybenzyl bromide
(6a, 35 μL, 0.28 mmol), acrylate (0.28 mmol), (CN)(H2O)Cby(OMe)7 (2, 27 mg, 0.025 mmol, 8 mol %), NaBH4 (19 mg, 0.5 mmol), Et3N (36
μL, 0.25 mmol), toluene (0.5 mL), 90 °C MW 300 W, 40 min.
a
reaction. The catalyst was recovered, purified, and reused post-
reaction (see Supporting Information (SI) for full optimization
tables). The reaction of benzyl bromide (3a) with phenyl vinyl
sulfone (4) was used in the optimization studies (Scheme 2).
The use of 3 equiv of benzyl bromide (3a) and 8 mol % of
catalyst 2 allowed isolation of product 5a in 63% yield (Table
1, entry 1). By decreasing the catalytic loading, using a higher
concentration of benzyl bromide (3a), or extending the
reaction time, a drop in yield was observed (entries 2−5), but
importantly in all cases ATRP or dehalogenation of the
product was not observed. With the optimal conditions in
hand, scope and limitation studies were undertaken (Scheme
3). Interestingly, replacing benzyl bromide (3a) with benzyl
chloride (3b) gave a sharp increase in the yield, giving
compound 5b in 82% yield. High yielding reactions were also
observed for 3-methoxybenzyl bromide (3c) and m-methyl-
benzyl bromide (3e). Expectedly, substrates possessing
electron-withdrawing groups (3h−l) gave products 5h−l in
only moderate yields (31−42%).
Table 1. Optimization Studies of ATRA Reaction
entry
3a (mmol)
2 (mol %)
time (min)
yield of 5 (%)
1
2
3
4
5
6
7
8
0.8
0.8
0.8
1.2
1.2
0.8
0.8
0.8
8
4
8
8
8
4
3
2
40
40
60
40
60
60
40
40
63
52
44
44
40
55
57
57
a
Conditions: benzyl bromide (3a), phenyl vinyl sulfone (4) (47 mg,
0.28 mmol), (CN)(H2O)Cby(OMe)7 (2, 27 mg, 0.025 mmol, 8 mol
%), NaBH4 (20 mg, 0.5 mmol), Cs2CO3 (85 mg, 0.26 mmol), toluene
(0.5 mL), 90 °C MW 300 W, 40 min.
and 7b in 15% and 52% yield, respectively. Notably, all
reactions proceeded considerably cleanly, lacking the expected
array of byproducts caused by dehalogenation of either a
substrate or a product. In the case of (1-bromoethyl)-benzene
(3g) only a slight decrease in the yield was found giving
compound 5g in 44% yield (18% d.e.). Isopropyl- (8a) or
octyl- (8b) bromides afforded products 9a and 9b in moderate
In the case of p-cyanobenzyl chloride (3l) an increase in the
yield, which occurred for substrate 3b, was not observed.
Furthermore, reactions with organic halides typically used in
ATRAs, CBr4 (6a), and CBrCl3 (6b), afforded compounds 7a
B
DOI: 10.1021/acs.orglett.7b03699
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yields bereft of the bromide substituent, presumably due to
either the Michael addition occurring or instant dehalogena-
tion of the ATRA product. In the case of dimethyl
bromomalonate (8c) unprecedented cyclopropanation was
observed, even though such a starting material is common in
ATRA studies. Cyclopropane 10 was isolated in 57% yield. In
this case, the presence of a base (Cs2CO3) might deprotonate
the ATRA product (traces of which were detected)
consequently inducing cyclization. Acrylates with α- or β-
methyl substituents failed to give desired products. This was
also true for halobenzenes and (2-bromoethyl)benzene.
Acrylates (11a−c) posed much more of a challenge, due to
polymerization or other side reactions occurring, mainly
ATRP, which viciously affected the yield. Consequently, an
excess of an acrylate must be used. In the case of methyl (11a)
and n-butyl acrylate (11c) the yield increased 2-fold to 42%
and 31% respectively. Interestingly, polymerization was not an
issue when using acrylamide (11d) that gave product 12d in
60% yield. (See SI for a full listing of the scope study.)
The proposed mechanism is presented in Scheme 4. The
reduction of catalyst 2a (Co(III)) gave supernucleophilic
16 can react with benzyl bromide 3a to also give intermediate
17 (J), which ultimately leads to product 18 or undergo
polymerization as well as other side reactions (K).
We have developed, to the best of our knowledge, the first
example of the selective cobalt-catalyzed ATRA reaction with
more common ATRP processes being suppressed. The
reaction is catalyzed by hydrophobic vitamin B12, a corrin
cobalt complex, giving products in decent yields. Benzyl
bromides and chlorides bearing electron-donating groups
furnished products in higher yields than those with electron-
withdrawing ones. Interestingly, utilization of aliphatic organic
halides led to products bereft of the halogen substituent, while
for dimethyl bromomalonate (8c) cyclopropane 10 formed
instead.
We assume that the reaction proceeds through a radical
mechanism involving dehalogenation of an organic halide by
the catalyst 2, followed by addition to an olefin followed by the
typical radical propagation.
This work displays vitamin B12 catalysis in a new light, in
terms of its relationship with organic halides. By fine-tuning
the reaction conditions, one can embrace the uniqueness of
this catalyst and expand its application beyond known
biochemical processes.
Scheme 4. Plausible Mechanism for the Vitamin B12
Catalyzed ATRA Reaction
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03699.
1
Experimental procedures, optimization studies, H and
13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dorot.gryko@icho.edu.pl.
*E-mail: keithoproinsias@gmail.
ORCID
Dorota Gryko: 0000-0002-5197-4222
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Science Centre (grant: SONATA 2013/11/D/T5/02956 and
OPUS no. 2016/21/B/ST5/03169).
Co(I) 2b (A), which upon reacting with benzyl bromide 3a
gave β-methyl substituted acrylates which failed to give the
desired products. This was also true for halobenzenes and (2-
bromoethyl)benzene cobalt complexes 13 (ESI-MS [M]+ 1127
and [M + CN]+ 1153) and 14 (ESI-MS [M + CN + Na]+
1215) (B). Following the homolytic cleavage radicals 15 (C)
and 16 (D) are liberated. This was further confirmed via the
addition of TEMPO, a radical trapping reagent, into the
reaction mixture, which halted the reaction confirming a
radical based reaction. Benzyl radical 15 then reacts with n-
butyl acrylate (11c) to give intermediate 17 (F), which was
also trapped with TEMPO (ESI-MS [M + Na]+ 398). Radical
15 can also undergo homocoupling, giving bibenzyl (E). In our
opinion, the mechanism adheres to a typical radical
propagation pathway (G), in which a second molecule of
benzyl bromide (3a) reacts with radical 17 forming desired
product 18 and benzyl radical 15. Alternatively, acrylate radical
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